The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63(+) bas...

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Bibliographic Details
Published in:Haematologica (Roma) Vol. 94; no. 11; pp. 1537 - 1545
Main Authors: PIERI, Lisa, BOGANI, Costanza, GUGLIELMELL, Paola, ZINGARIELLO, Maria, ALBA RANA, Rosa, BARTALUCCI, Niccolò, BOSI, Alberto, VANNUCCHI, Alessandro M
Format: Journal Article
Language:English
Published: Pavia Ferrata Storti Foundation 01-11-2009
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Basophils - immunology
Basophils - pathology
Biological and medical sciences
Diseases of red blood cells
Female
Hematologic and hematopoietic diseases
Humans
Hypersensitivity - genetics
Janus Kinase 2 - genetics
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical sciences
Middle Aged
Mutation, Missense
Original
Polycythemia Vera - genetics
Polycythemia Vera - immunology
Polycythemia Vera - pathology
Polycythemias
Pruritus - etiology
Young Adult
Human
Skin disease
Agonist
Hematology
Hypersensitivity
Granulocyte
Polycythemia vera
Hemopathy
Pruritus
Basophil
Constitutive mutation
Myeloproliferative syndrome
Genetics
JAK2V647F mutation
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Summary:The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63(+) basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. We found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63(+) basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63(+) basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. These data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells' abnormal function and, putatively, in the pathogenesis of pruritus.
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ISSN:0390-6078
1592-8721
DOI:10.3324/haematol.2009.007047